tbuckley/cabot-search huggingface dataset:
Abstract 881: Desmocollin-3 and tumor immune microenvironment: Bioinformatics evaluation
Authors: Arpit Dheeraj, Bakulesh M. Khamar, Chandreshwar P. Shukla, Nayan K. Jain, Rajiv I. Modi
Journal: Cancer Research (2023)

Abstract Desmocollin-3 (DSC3) is a desmosomal adhesion molecule responsible for integrity and cell adhesion under normal physiological condition. Its expression is altered during carcinogenesis. DSC3 is a p53 responsive gene. Like other adhesion molecules, it is described to provide barrier for immune infiltration of tumor. To identify a specific immune gene signature related to DSC3, spearman correlation coefficient was determined for 207 immune related genes using Cbioportal in cancer having high and low level of DSC3 gene expression .We classified renal adenocarcinoma lung, hepatocellular carcinoma and renal cancer as DSC3low and squamous lung cancer, cervical cancer and head and Neck cancer as DSC3high based on DSC3 gene expression level. In DSC3high group, six genes were found to be correlated (Spearman correlation ≥ 0.3) with DSC3 expression (Table), while none of the 207 immune related genes were correlated with DSC3low expression. Of genes with positive correlation, CD44 is a marker for stem cell and is associated with resistance to chemotherapy while S100A12 and TOLLIP are associated with carcinogenesis and inflammation. Of immune genes with negative correlation, GATA6 is a tumor suppressive gene, IL-12A is responsible for T-cell-independent induction of IFNγ and CD63 is associated with survival as described in lung cancer. This findings suggests DSC3high expression may be associated with poor prognosis compared DSC3low . DSC3 expression is specific for squamous lung cancer and is used to differentiate it from adenocarcinoma lung. Squamous lung cancer is also known to have poor prognosis compared to adenocarcinoma of lung. We will be presenting full details about 207 selected genes and their correlation with DSC3 in our presentation. Table: Spearman’s correlation of DSC3 with Immune genes DSC3 expression Immune genes with positive spearman’s correlation Immune genes with negative spearman’s correlation Cancer Median RSEM (N) CD44 S100A12 TOLLIP CD63 GATA6 IL12A LUSC 6208 (n=501) 0.4 0.3 0.4 -0.4 -0.3 -0.3 CESC 10086 (n=306) 0.6 0.6 0.6 -0.6 -0.4 -0.4 HNSC 15287(n=522) 0.3 0.3 0.3 -0.5 -0.3 -0.4 KIPAN 1.5 (n=720) &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 LIHC 2.0 (n=231) &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 LUAD 10 (n=496) &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 &amp;lt; 0.3 Citation Format: Arpit Dheeraj, Bakulesh M. Khamar, Chandreshwar P. Shukla, Nayan K. Jain, Rajiv I. Modi. Desmocollin-3 and tumor immune microenvironment: Bioinformatics evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 881.
Abstract 1138: Novel SMARCA2 degrading bifunctional molecules as therapeutics in <i>SMARCA4</i> mutant lung cancer
Authors: Sasi Kotagiri, Nicholas Blazanin, Yuanxin Xi, Jing Wang, Yonathan Lissanu
Journal: Cancer Research (2023)

Abstract Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports, and our own data, have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Using global proteomic analysis and quantification of more than 8000 proteins, we showed that our SMARCA2 PROTAC is highly selective for SMARCA2. Importantly, we showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells in vitro. Mechanistically, we demonstrated that YD23 reduces chromatin accessibility only in SMARCA4 deficient cells. In particular, YD23 profoundly decreased chromatin accessibility at enhancers of a number of genes including cell cycle and cell growth regulatory genes. Gene expression profiling and pathway analysis indicated that various cell cycle genes were downregulated by YD23 consistent with the reduced chromatin accessibility at their regulatory regions. In conclusion, our study provides a potent chemical probe for studying the synthetic lethal interaction between SMARCA2 and SMARCA4, dissect the chromatin and epigenetic landscape alterations and lay the foundation for future preclinical and clinical development of SMARCA2 degraders as therapeutics. Citation Format: Sasi Kotagiri, Nicholas Blazanin, Yuanxin Xi, Jing Wang, Yonathan Lissanu. Novel SMARCA2 degrading bifunctional molecules as therapeutics in SMARCA4 mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1138.
Abstract 1283: MUC5AC promotes brain metastases and colonization in non small cell lung cancer
Authors: Sanjib Chaudhary, Shailendra Kumar Maurya, Jawed Siddiqui, Mohd W. Nasser, Surinder K. Batra, Imayavaramban Lakshmanan, Apar Kishor Ganti
Journal: Cancer Research (2023)

Abstract Background: Non-small cell lung adenocarcinoma (NSCLC), constitutes 80-85% of the lung cancers. The 5-year survival of patients with metastatic lung cancer is only 5%. Additionally, the prognosis worsens in NSCLC patients (40-50%) that have developed brain metastasis. Mucin 5AC (MUC5AC) is overexpressed in the primary NSCLC and brain metastatic tissues; however, the mechanism in the MUC5AC-mediated brain metastasis is unclear. Methods: Immunohistochemistry was performed on lung cancer samples. Expression studies were conducted in the brain-tropic cell lines (A549-BrM, PC9-BrM, and HCC4006-BrM cells) and their respective parental lines. CRISPR Cas9 or shRNA was used to either knockout/knockdown MUC5AC in the cell lines. Mass-spectrometry analysis and protein arrays were conducted in the brain trophic cells. In vivo mouse models involving intracardiac injection of cancer cells were performed, and the effect of MUC5AC brain metastasis and survival was analyzed. Results: MUC5AC was significantly increased in NSCLC brain metastatic tissues. Similarly, MUC5AC expression was elevated in NSCLC brain tropic (BrM) cell lines compared to parental lines. Treatment of BrM or parental cells with the conditioned media of normal human astrocytes resulted in increased MUC5AC levels. We observed astrocyte-derived CCL2-induced the MUC5AC expression in both parental and BrM cells. Mass-spectrometry based proteomic analysis indicated decreased cell adhesion molecules such as ALCAM, ITGB4, ITGB5, CDH17, and DSG2 in MUC5AC knockdown tropic cells. Further, Mass-spectrometry based interactome studies revealed MUC5AC interaction with Annexin A2 enabling the cancer cell adhesion. Intracardiac injection of MUC5AC knockdown A549-BrM (A549-BrM-shMUC5AC) cells showed a significant reduction in brain metastasis and increased survival of the mice compared to scramble control group (P&amp;lt;0.001). Conclusion: Our study identified the role of MUC5AC in metastasis and colonization in the brain environment. Mechanistically, MUC5AC interacts with the Annexin A2 during metastasis, while astrocyte derived CCL2 further induced the MUC5AC expression facilitating the colonization of the NSCLC cells in the brain. Hence, targeting MUC5AC and its interactions partner Annexin A2 may prevent NSCLC brain metastasis. Citation Format: Sanjib Chaudhary, Shailendra Kumar Maurya, Jawed Siddiqui, Mohd W. Nasser, Surinder K. Batra, Imayavaramban Lakshmanan, Apar Kishor Ganti. MUC5AC promotes brain metastases and colonization in non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1283.
Abstract 3672: RNA epigenetic regulation of cholesterol metabolism in neuroblastoma
Authors: Mohit Bansal, Anamika Gupta, Han-Fei Ding
Journal: Cancer Research (2023)

Abstract Pseudouridylation (conversion of uridine to pseudouridine) is a common epigenetic modification of RNA which increases its structural stability. RNA pseudouridylation is catalyzed by the family of pseudouridine synthases (PUS). The functional significance and biological relevance of mRNA pseudouridylation are poorly understood. Here we report that the oncogene MYCN, which drives the development of high-risk neuroblastoma, transcriptionally upregulates the PUS1 gene. Further, examination of gene expression profiling data from neuroblastoma patients (the SEQC dataset) reveals that higher PUS1 expression is associated with poor prognosis. The transcriptional upregulation of PUS1 expression in MYCN amplified cell lines is of functional significance, as our studies reveals that knockdown of PUS1 expression in neuroblastoma cell lines suppresses cell survival and proliferation. Our RNA-seq analysis reveals that a key downstream target of PUS1 is cholesterol metabolism. PUS1 knockdown reduces the expression of key enzymes in the mevalonate pathway for cholesterol synthesis. Mechanistically, PUS1 may targets SREBP2, a master regulator of cholesterol metabolism responsible for transcriptional upregulation of enzymes for cholesterol biosynthesis. We showed that PUS1 expression is essential for maintaining SREBP2 expression in MYCN-amplified neuroblastoma cells and for statin-induced feedback activation of the mevalonate pathway, a commonly used system for assessing the transcriptional activity of SREBP2. These findings suggest that a function of PUS1 in sustaining the proliferation of neuroblastoma cells is to promote cholesterol metabolism, which could be exploited as a therapeutic strategy against high-risk neuroblastoma. Citation Format: Mohit Bansal, Anamika Gupta, Han-Fei Ding. RNA epigenetic regulation of cholesterol metabolism in neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3672.
Abstract 3723: Identification and functional characterization of long noncoding RNAs that regulate TGF-&amp;lt;&amp;946;&amp;gt;-Smad pathway as Smad co-factors
Authors: Masatoshi Kitagawa, Kosuke Ota, Tatsuya Ohhata, Satoshi Sakai
Journal: Cancer Research (2023)

Abstract TGF-β-Smad pathway participates in various biological processes such as development, differentiation, growth regulation, and cancer progression including epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) also involved in carcinogenesis and cancer malignancies. To identify lncRNAs regulating TGF-β-Smad pathway, we comprehensively identified lncRNAs induced by TGF-β and found and reported a lncRNA ELIT-1 (EMT-associated lncRNA induced by TGF-β-1) which was induced by TGF-β and promoted EMT by facilitating TGF-β-Smad signaling. ELIT-1 bound to Smad and participated in expression of TGF-β target genes including Snail. Prognosis of lung adenocarcinoma and gastric cancer patients with high expression of ELIT-1 was poor suggesting that ELIT-1 may be useful as a novel prognostic and therapeutic target. Recently, we found that lincNMR (long intergenic noncoding RNA-nucleotide metabolism regulation) was induced via TGF-β-Smad pathway in various cell lines. Moreover, RNA-seq analysis using lincNMRs-depleted cells indicated that lincNMRs was involved in expression of APOBEC3B, a cytidine deaminase, promoting C to U mutation and highly expressed in various human cancers. Although, regulatory mechanisms of APOBEC3B expression have not been fully elucidated, we proved that lincNMRs bound to Smad and promoted the activity of APOBEC3B promoter. These data suggest that lincNMRs participate in APOBEC3B expression by collaborating with TGF-β-Smad pathway. Additionally, high expression of lincNMRs was positively correlated with high expression of APOBEC3B in various cancer cell lines. The high expression of APOBEC3B as well as lincNMR was significantly associated with their poor prognosis in liver and lung cancer patients, suggesting that lincNMR may contribute to tumor malignancy by enhanced expression of APOBEC3B via TGF-β-Smad pathway. Citation Format: Masatoshi Kitagawa, Kosuke Ota, Tatsuya Ohhata, Satoshi Sakai. Identification and functional characterization of long noncoding RNAs that regulate TGF-&amp;lt;&amp;946;&amp;gt;-Smad pathway as Smad co-factors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3723.
Abstract 2272: Targeting the chaperone Hsp90 to activate the immune system and eradicate the triple negative breast cancer
Authors: Nada Eisa, Vincent M. Crowley, Asif Elahi, Vamsi K. Kommalapati, Hasan Korkaya, Abdessamad Debbab, Brian Blagg, Ahmed Chadli
Journal: Cancer Research (2023)

Abstract Low response rates and immune-related adverse events limit the impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) with these inhibitors limited their clinical efficacy as monotherapies. We discovered that Enniatin A (EnnA) binds to the interface between the middle domains of the Hsp90 dimer and destabilizes Hsp90 client oncoproteins without inducing an HSR. EnnA induces cancer cell immunogenic cell death in aggressive breast cancer models and exhibits superior anti-tumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment in syngeneic mouse models to promote CD8+ T cell-dependent anti-tumor activity mediated through a reduced level of PD-L1 and activation of CX3CR1 pathway. We propose that EnnA is a promising anti-tumor agent with a mechanism of action involving immunogenic cancer cell toxicity and mobilization of CD8+ T cells into the tumor site. Citation Format: Nada Eisa, Vincent M. Crowley, Asif Elahi, Vamsi K. Kommalapati, Hasan Korkaya, Abdessamad Debbab, Brian Blagg, Ahmed Chadli. Targeting the chaperone Hsp90 to activate the immune system and eradicate the triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2272.
Abstract 3719: Targeting the eIF6 and 60S ribosomal subunit interaction interface in cancers
Authors: Kavya Meena Harish, Aparna Biswas, Poonam Roshan, Sofia Origanti
Journal: Cancer Research (2023)

Abstract Translational control is integral to cancer initiation and progression. A subset of translation initiation factors are deregulated in cancers to facilitate their rampant growth and proliferation. Eukaryotic translation initiation factor 6 (eIF6) is one such factor that is over expressed in many cancers including lung, colon, ovarian and breast cancers, and deregulation of eIF6 is correlated with a poor cancer prognosis. Association of eIF6 with 60S is critical for 60S assembly. However, eIF6 must be released from 60S prior to translation to permit inter subunit interactions between 60S and 40S and to facilitate the formation of translationally proficient 80S complex. Release of eIF6 is deregulated in the ribosomopathy- Shwachman Diamond Syndrome that is predisposed to leukemias. Also, loss of eIF6 markedly delays tumorigenesis without affecting normal growth, which presents eIF6 as a viable therapeutic target. A potential therapeutic strategy is to target the eIF6 and 60S ribosomal interaction interface. Through extensive biophysical analyses, we had identified residues that are critical for the interaction between eIF6 and 60S ribosomal subunit. We show that targeting these key residues in the eIF6-60S interaction interface markedly delays colonic cancer growth and inhibits protein synthesis. Interestingly, targeting eIF6 leads to an upregulation of p53 independent of the DNA damage response, suggesting that ribosomal stress contributes to the stabilization of p53. Future studies will determine the mRNA targets that are translationally deregulated by inactivation of eIF6. We will also determine the effect of targeting eIF6 function in inhibiting tumor growth and progression in vivo. Citation Format: Kavya Meena Harish, Aparna Biswas, Poonam Roshan, Sofia Origanti. Targeting the eIF6 and 60S ribosomal subunit interaction interface in cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3719.
Abstract 3428: Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13
Authors: Yu Chang, Jianzhang Yang, Jean Ching-Yi Tien, Zhen Wang, Yang Zhou, Pujuan Zhang, Weixue Huang, Josh Vo, Ingrid J. Apel, Cynthia Wang, Victoria Zhixuan Zeng, Yunhui Cheng, Shuqin Li, George Xiaoju Wang, Ke Ding, Arul M. Chinnaiyan
Journal: Cancer Research (2023)

Abstract Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 nM and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved anti-proliferative activity compared to the structurally similar inhibitor 4.The 2nd generation CDK12/13 degrader 9069 was further developed, which showed more potent degradation on both CDK12 and CDK13. Interestingly, multiple prostate cancer cell lines were sensitive to 9069, such as VCaP, 22RV1 and LAPC4 with IC50 values of 22.9, 90.3 and 152.1 nM, respectively. In vivo studies showed a potent tumor growth inhibition in both VCaP CRPC xenograft and PC310 PDX prostate cancer models. These results suggest the potential application of a CDK12/13 degrader for the treatment of TNBC and prostate cancer. Citation Format: Yu Chang, Jianzhang Yang, Jean Ching-Yi Tien, Zhen Wang, Yang Zhou, Pujuan Zhang, Weixue Huang, Josh Vo, Ingrid J. Apel, Cynthia Wang, Victoria Zhixuan Zeng, Yunhui Cheng, Shuqin Li, George Xiaoju Wang, Ke Ding, Arul M. Chinnaiyan. Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3428.
Abstract 3429: Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes
Authors: Yujia Zhang, Jessica Bates, Benoit Gourdet, Louise Birch, Philip Addis, Roland Hjerpe, Allan M. Jordan
Journal: Cancer Research (2023)

Abstract Molecular glue degraders are compact, low molecular weight molecules that can efficiently induce specific and potent degradation of a target protein. This class of degraders function by inducing interactions between a target of interest and a ubiquitin-ligase, either by stabilization of weak pre-existing interactions, or by generation of entirely novel interactions. These molecules offer significant opportunity beyond heterobifunctional degraders such as PROTACs, not least in terms of improved molecular properties. However, beyond the IMID molecular glues, typified by thalidomide, pomalidomide and lenalidomide, novel molecular glue chemotypes remain scarce. To address this need, we have developed biophysics-based molecular glue screening platform, exploiting our internal, high quality fragment library and proximity-based screening platforms to rapidly identify promising new molecular glues for further optimization. A potential advantage of utilizing cell-free biophysical systems is the opportunity to select both the target and the desired ligase, opening up for development of degraders that capitalize upon differential expression of ligases in different tissues. As proof of concept, we have applied this platform to find new molecular glues to degrade CK1α. This Ser/Thr kinase has been found to be over-expressed in metastatic colorectal cancer, and this over-expression correlates with poor overall survival. The kinase has also been implicated as an oncogenic driver in tumors such as B-Cell lymphomas and non-Hodgkin lymphomas, suggesting a potential therapeutic application for novel CK1α molecular glues. Utilizing known IMID-derived molecular glues between CK1α and CRBN as benchmark controls, we identified several non-IMID derived chemotypes as tentative stabilizers of the CRBN/CK1α interaction. Further studies on these novel candidate degrader templates are now underway. Citation Format: Yujia Zhang, Jessica Bates, Benoit Gourdet, Louise Birch, Philip Addis, Roland Hjerpe, Allan M. Jordan. Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3429.